Cardiorespiratory fitness and survival following cancer diagnosis.

AIMS: Data on the association of cardiorespiratory fitness with survival of cancer patients are limited. This study aimed to evaluate the association between midlife cardiorespiratory fitness and survival after a subsequent cancer diagnosis. METHODS: We evaluated 19,134 asymptomatic self-referred adults who were screened in preventive healthcare settings. All subjects were free of cardiovascular disease and cancer at baseline and completed a maximal exercise stress test. Fitness was categorised into age-specific and sex-specific quintiles according to the treadmill time and dichotomised to low (quintiles 1-2) and high fitness groups. RESULTS: The mean age was 50 ± 8 years and 72% were men. During a median follow-up of 13 years (interquartile range 7-16) 517 (3%) died. Overall, 1455 (7.6%) subjects developed cancer with a median time to cancer diagnosis of 6.4 years (interquartile range 3-10). Death from the time of cancer diagnosis was significantly lower among the high fitness group (Plog rank = 0.03). Time-dependent analysis showed that subjects who developed cancer during follow-up were more likely to die (P < 0.001). The association of cancer with survival was fitness dependent such that in the lower fitness group cancer was associated with a higher risk of death, whereas among the high fitness group the risk of death was lower (hazard ratio 20 vs. 15; Pfor interaction = 0.047). The effect modification persisted after applying a 4-year blanking period between fitness assessment and cancer diagnosis (Pfor interaction = 0.003). CONCLUSION: Higher midlife cardiorespiratory fitness is associated with better survival among cancer patients. Our findings support fitness assessment in preventive healthcare settings.

Heart Failure Due to High-Degree Atrioventricular Block: How Frequent Is It and What Is the Cause?

BACKGROUND: The causes of heart failure (HF) during high-grade atrioventricular block (AVB) are poorly understood. This study assessed the mechanisms of HF in patients with AVB. METHODS: We studied patients presenting (between 2012 and 2016) with high-grade AVB not related to acute myocardial infarction. Patients with preexisting significant valvular heart disease were excluded. All patients underwent comprehensive echocardiographic evaluation during AVB, before pacemaker implantation. The diagnosis of HF was based on the Framingham criteria. RESULTS: A total of 122 patients were included in the study, 50% male, average age 76 ± 13 years. Twenty-eight patients (23%) with AVB presented with HF. Univariate correlates associated with HF were decrease in cardiac output (CO) (odds ratio [OR] 0.68 [95% confidence interval 0.49-0.9] per L/min; P = 0.007), measures of impaired left ventricular (LV) compliance, and increase in diastolic mitral regurgitation (MR) volume (OR 1.04 [1.01-1.07] per cc; P = 0.0016). Ventricular rate during AVB and LV ejection fraction were not significantly associated with the presence of HF. By multivariate nominal logistic analysis, the best model associated with HF included diastolic MR volume (OR 1.04 [1.001-1.09]; P = 0.02), A-wave deceleration time (OR 0.96 [0.94-0.9]; P = 0.001), and CO (OR 0.92 [0.4-1.00]; P = 0.005) (χ2 = 30.6; area under the receiver operating characteristic curve = 0.84; P < 0.0001 for the entire model). CONCLUSIONS: In the setting of high-degree AVB, clinical HF occurrence correlates with impaired LV compliance and diastolic MR volume, but not with heart rate or LV ejection fraction. The cardiac performance of patients with poor LV compliance and high-volume diastolic MR may show maladjustment to slow heart rates, manifesting as low CO and HF.

Cardiovascular Toxicities of Antiangiogenic Tyrosine Kinase Inhibitors: A Retrospective, Pharmacovigilance Study.

BACKGROUND: Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) are an essential therapeutic option in the management of various solid tumors, particularly renal cell carcinoma (RCC). However, post-marketing data regarding their potential cardiovascular toxicities are scant. OBJECTIVE: To identify and characterize cardiovascular adverse events (CVAEs) of VEGFR-TKIs indicated for RCC. PATIENTS AND METHODS: Disproportionality analysis of the US Food and Drug Administration adverse event reporting system (July 2014-December 2019) using the reporting odds ratio (ROR) and the lower bound of the Information component (IC) 95% credibility interval (IC025 > 0 is significant). RESULTS: We identified 51,836 adverse event reports of sunitinib, pazopanib, axitinib, cabozantinib, and lenvatinib in the full database [36% women; median age 65 years (range 57-73)]. CVAEs accounted for 11,784 (23%) of the reports, with hypertension [n = 5548 (11%), ROR = 6.55 (95% CI 6.37-6.74), IC025 = 2.48] and hemorrhages [n = 3710 (7.2%), ROR = 1.28 (1.24-1.32), IC025 = 0.28] being the most frequent types. Additional CVAEs were over-reported with VEGFR-TKIs treatment, including aortic dissection [n = 61 (0.1%), ROR = 3.50 (2.71-4.51)], pericardial diseases [n = 173 (0.3%), ROR = 1.98 (1.70-2.30)], cardiomyopathy [n = 61 (0.1%), ROR = 1.89 (1.47-2.43)], heart failure [n = 868 (1.7%), ROR = 1.35 (1.26-1.44)], and venous thromboembolism [n = 604 (1.2%), ROR = 1.33 (1.23-1.45), all IC025 > 0]. The major pericardial disorder was non-malignant pericardial effusion [n = 134 (77%)]. Aortic dissections were also over-reported in patients without concomitant elevated blood pressure [ROR = 2.68 (1.97-3.63), IC025 = 0.91]. Finally, CVAEs were reported more often following lenvatinib and sunitinib treatment compared to other VEGFR-TKIs. CONCLUSIONS: In post-marketing surveillance data, VEGFR-TKIs are associated with increased reporting of various CVAEs, including pericardial diseases, particularly non-malignant pericardial effusion, and aortic dissections. Moreover, VEGFR-TKIs differ in their CVAE reporting patterns. Clinicians should be conscious of these findings in the care of VEGFR-TKIs recipients.

Grapefruit juice prolongs the QT interval of healthy volunteers and patients with long QT syndrome.

BACKGROUND: The list of medications linked to drug-induced long QT syndrome (LQTS) is diverse. It is possible that food products too have QT-prolonging potential. OBJECTIVE: We tested the effects of grapefruit juice on the QT interval with the methodology used by the pharmaceutical industry to test new drugs. METHODS: This was an open-label, randomized, crossover study with blinded outcome evaluation, a thorough QT study of grapefruit juice performed according to the Guidelines for the Clinical Evaluation of QT/QTc for Non-antiarrhythmic Drugs. Thirty healthy volunteers and 10 patients with congenital LQTS were studied. Healthy volunteers drank 2 L of grapefruit juice (in divided doses), or received 400 mg oral moxifloxacin, in a randomized crossover study. Patients with LQTS were tested with only grapefruit. Repeated baseline, off-drug, and on-drug (grapefruit or moxifloxacin) electrocardiograms were scanned and coded. QT measurements were done with electronic calipers. RESULTS: In comparison to off-drug electrocardiograms, grapefruit juice led to significant rate-corrected QT (QTc) prolongation. The absolute net QTc prolongation from grapefruit was 14.0 ms (95% confidence interval 6.2-21.7 ms; P < .001). The QT-prolonging effects of grapefruit in healthy volunteers were comparable with those of moxifloxacin. The QT-prolonging effects of grapefruit juice were greater in female patients and particularly marked in patients with LQTS (net QTc prolongation 21.8 ms; 95% confidence interval 3.4-35.3 ms; P = .034). CONCLUSION: Grapefruit juice, at doses tested, prolongs the QT interval. The effect is significant in healthy volunteers, greater in female patients, and more so in patients with LQTS.

The "Burden" of Malignancy in a Tertiary Hospital Intensive Cardiovascular Care Unit.

OBJECTIVES: During the past decade, the most common causes of mortality and morbidity were cardiovascular diseases and malignancies. The aim of the current study was to describe the incidence, course of admission, and short-term (30-day) prognosis of patients with and without malignancy, admitted to a tertiary center intensive cardiovascular care unit (ICCU). METHODS: A prospective observational study of 2,259 patients admitted to the ICCU was conducted between January 2014 and December 2015. Patients with malignancies (n = 256) were divided into 2 groups: those with solid and those with homogenous tumors. RESULTS: The time of diagnosis was categorized into 3 patient groups: recent (<6 months), 59 patients (23%); late (6-24 months), 49 patients (19%), and very late (>24 months), 148 patients (58%). Those with a history of malignancy were older (73 ± 12 vs. 64 ± 15, p < 0.001) and were more likely to be female (p = 0.002). After using a multivariate logistic regression model analysis, no differences were found in therapeutic interventions and clinical outcomes, including major bleeding and acute renal failure, between patients with and without malignancies. CONCLUSIONS: Patients with a malignancy comprised about 10% of the entire ICCU population. While mortality was independently associated with advanced age, renal failure, and a diagnosis of ST-elevation myocardial infarction, malignancy alone was not found to be independently associated with a higher mortality rate at 30 days of follow-up.

Safety of Outpatient Initiation of Disopyramide for Obstructive Hypertrophic Cardiomyopathy Patients.

BACKGROUND: Disopyramide is effective in ameliorating symptoms in patients with hypertrophic cardiomyopathy; however, its potential for proarrhythmic effect has raised concerns about its use in the ambulatory setting. The risk of initiating disopyramide in this manner has never been evaluated. METHODS AND RESULTS: All charts of patients seen in the outpatient hypertrophic cardiomyopathy clinic between 2010 and 2014 were screened for initiation of disopyramide and data were extracted. Disopyramide in our clinic is usually initiated at a dose of 300 mg daily and titrated during follow-up. A total of 2015 patients were seen in the clinic, including 168 who were started on disopyramide. There were no cardiac events within 3 months of disopyramide initiation. During long-term follow-up (255 patient-years; mean, 447 days; interquartile range, 201-779), only 2 patients developed cardiac events (syncope of unknown cause in both). Thirty-eight patients (23%) developed side effects of disopyramide and 18 (11%) stopped the drug because of these side effects. Of the patients continuing disopyramide long term, 63% remained free of septal reduction interventions at end of follow-up. Disopyramide at a dose of 300 mg prolonged the mean QTc interval by 19±23 ms; however, increasing the dose to 600 mg had no further significant effect. CONCLUSIONS: Initiation of disopyramide in the outpatient setting is safe and the risk of subsequent sudden cardiac death is low. Because of its QT-prolonging effect, precautions may be necessary in patients at higher risk of torsades de pointes.

Prevalence and Clinical Implication of Double Mutations in Hypertrophic Cardiomyopathy: Revisiting the Gene-Dose Effect.

BACKGROUND: Available data suggests that double mutations in patients with hypertrophic cardiomyopathy are not rare and are associated with a more severe phenotype. Most of this data, however, is based on noncontemporary variant classification. METHODS AND RESULTS: Clinical data of all hypertrophic cardiomyopathy patients with 2 rare genetic variants were retrospectively reviewed and compared with a group of patients with a single disease-causing variant. Furthermore, a literature search was performed for all studies with information on prevalence and outcome of patients with double mutations. Classification of genetic variants was reanalyzed according to current guidelines. In our cohort (n=1411), 9% of gene-positive patients had 2 rare variants in sarcomeric genes but only in 1 case (0.4%) were both variants classified as pathogenic. Patients with 2 rare variants had a trend toward younger age at presentation when compared with patients with a single mutation. All other clinical variables were similar. In data pooled from cohort studies in the literature, 8% of gene-positive patients were published to have double mutations. However, after reanalysis of reported variants, this prevalence diminished to 0.4%. All patients with 2 radical mutations in MYBPC3 in the literature had severe disease with death or heart transplant during the first year of life. Data on other specific genotype-phenotype correlations were scarce. CONCLUSIONS: Double mutations in patients with hypertrophic cardiomyopathy are much less common than previously estimated. With the exception of double radical MYBPC3 mutations, there is little data to guide clinical decision making in cases with double mutations.

Lack of Phenotypic Differences by Cardiovascular Magnetic Resonance Imaging in MYH7 (ß-Myosin Heavy Chain)- Versus MYBPC3 (Myosin-Binding Protein C)-Related Hypertrophic Cardiomyopathy.

BACKGROUND: The 2 most commonly affected genes in hypertrophic cardiomyopathy (HCM) are MYH7 (ß-myosin heavy chain) and MYBPC3 (ß-myosin-binding protein C). Phenotypic differences between patients with mutations in these 2 genes have been inconsistent. Scarce data exist on the genotype-phenotype association as assessed by tomographic imaging using cardiac magnetic resonance imaging. METHODS AND RESULTS: Cardiac magnetic resonance imaging was performed on 358 consecutive genotyped hypertrophic cardiomyopathy probands at 5 tertiary hypertrophic cardiomyopathy centers. Genetic testing revealed a pathogenic mutation in 159 patients (44.4%). The most common genes identified were MYH7 (n=53) and MYBPC3 (n=75); 33.1% and 47% of genopositive patients, respectively. Phenotypic characteristics by cardiac magnetic resonance imaging of these 2 groups were similar, including left ventricular volumes, mass, maximal wall thickness, morphology, left atrial volume, and mitral valve leaflet lengths (all P=non-significant). The presence of late gadolinium enhancement (65% versus 64%; P=0.99) and the proportion of total left ventricular mass (%late gadolinium enhancement; 10.4±13.2% versus 8.5±8.5%; P=0.44) were also similar. CONCLUSIONS: This multicenter multinational study shows lack of phenotypic differences between MYH7- and MYBPC3-associated hypertrophic cardiomyopathy when assessed by cardiac magnetic resonance imaging. Postmutational mechanisms appear more relevant to thick-filament disease expression and outcome than the disease-causing variant per se.

Exercise in patients with hypertrophic cardiomyopathy: A review of current evidence, national guideline recommendations and a proposal for a new direction to fitness.

Hypertrophic cardiomyopathy is a common genetic disorder with a prevalence of 1:500 in the general population. Amongst a varied spectrum of clinical presentations, the most feared complication of this cardiac disorder is sudden cardiac death. Although only a minority of patients with hypertrophic cardiomyopathy who suffer sudden cardiac death or resuscitated cardiac arrest do so during exercise, strenuous physical activity is regarded as an important trigger for these tragic outcomes. Furthermore, during exercise, patients with hypertrophic cardiomyopathy may develop augmentation of left ventricular outflow tract obstruction, myocardial ischemia, diastolic dysfunction and/or inappropriate vasodilation in non-exercising vascular beds. This in turn may lead to exertional dyspnea, chest pain or syncope. Accordingly, patients with hypertrophic cardiomyopathy are disqualified from competitive sports and in many cases are recommended to avoid strenuous physical activity of any kind. Nevertheless, avoidance of physical activity comes with a price. The positive effects of regular exercise have been extensively reported to convey a wide range of benefits including reduced cardiovascular events, weight reduction and improved wellbeing. Therefore, finding the right exercise level that will offer some of the benefits of physical activity without increasing the risk of sudden cardiac death is of utmost importance. In this review, we discuss the current evidence for and against exercise in this patient population and review national guideline recommendations. We also propose alternative fitness strategies including a novel fitness program implemented by our hypertrophic cardiomyopathy center which may be of particular usefulness for hypertrophic cardiomyopathy patients.

Usefulness of 14-Day Holter for Detection of Nonsustained Ventricular Tachycardia in Patients With Hypertrophic Cardiomyopathy.

Nonsustained ventricular tachycardia (NSVT), defined as ≥3 consecutive ventricular beats at ≥120 beats/min lasting <30 seconds, is an independent predictor of sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HC). Current guidelines recommend 24- to 48-hour Holter monitoring as part of SCD risk stratification. We sought to assess the difference in diagnostic yield of 14-day Holter monitoring compared to 24-48 hours for the detection of NSVT and to assess the prevalence and characteristics of NSVT in patients with HC with prolonged monitoring. We retrospectively analyzed the 14-day Holter monitors of 77 patients with HC from May 2014 to March 2016. Number of episodes and maximal length and rate on each day were recorded. NSVT was detected in 75.3% of patients during 14-day Holter monitoring. The median number of runs was 2 (range 0 to 26 runs). The median number of beats of the longest run was 10.5 (range 3 to 68 beats) with a mean maximum rate of 159.5 ± 20.8.4 beats/min (range 102 to 203 beats/min). First episodes of NSVT were detected throughout the 14 days, with only 22.5% and 44.8% of the episodes captured within the first 24 and 48 hours of monitoring, respectively. In conclusion, prolonged Holter monitoring revealed ≥1 episode of NSVT in 75% of patients with HC of which <50% were detected within the first 48 hours. Hence, prolonged Holter monitoring may be superior for SCD risk stratification in HC. However, the high prevalence of NSVT in this population may limit its utility in evaluating the risk for SCD of the individual patient.

Provocation of sudden heart rate oscillation with adenosine exposes abnormal QT responses in patients with long QT syndrome: a bedside test for diagnosing long QT syndrome.

AIMS: As arrhythmias in the long QT syndrome (LQTS) are triggered by heart rate deceleration or acceleration, we speculated that the sudden bradycardia and subsequent tachycardia that follow adenosine injection would unravel QT changes of diagnostic value in patients with LQTS. METHODS AND RESULTS: Patients (18 LQTS and 20 controls) received intravenous adenosine during sinus rhythm. Adenosine was injected at incremental doses until atrioventricular block or sinus pauses lasting 3 s occurred. The QT duration and morphology were studied at baseline and at the time of maximal bradycardia and subsequent tachycardia. Despite similar degree of adenosine-induced bradycardia (longest R-R 1.7+/-0.7 vs. 2.2+/-1.3 s for LQTS and controls, P=NS), the QT interval of LQT patients increased by 15.8+/-13.1%, whereas the QT of controls increased by only 1.5+/-6.7% (P<0.001). Similarly, despite similar reflex tachycardia (shortest R-R 0.58+/-0.07 vs. 0.55+/-0.07 s for LQT patients and controls, P=NS), LQTS patients developed greater QT prolongation (QTc=569+/-53 vs. 458+/-58 ms for LQT patients and controls, P<0.001). The best discriminator was the QTc during maximal bradycardia. Notched T-waves were observed in 72% of LQT patients but in only 5% of controls during adenosine-induced bradycardia (P<0.001). CONCLUSION: By provoking transient bradycardia followed by sinus tachycardia, this adenosine challenge test triggers QT changes that appear to be useful in distinguishing patients with LQTS from healthy controls.